Method of enhancing circulation with piperazines

ABSTRACT

Novel N-(trimethoxybenzyl)-piperazines of the formula: ##STR1## wherein A= ##STR2## wherein R is trifluoromethyl, hydroxy, nitro, halogen, lower-alkyl, or lower-alkoxy; 
     R&#39; is hydrogen, trifluoromethyl, halogen, lower-alkyl, or lower-alkoxy; 
     R&#34; is hydrogen or lower-alkoxy, 
     or wherein R and either R&#39; or R&#34; together stand for lower-alkylene dioxy, and acid addition salts thereof, a method of preparing same, pharmaceutical compositions thereof, and a method of enhancing circulation, especially cerebrovascular circulation, therewith, are disclosed.

This is a division of application Ser. No. 181,189, filed Aug. 22, 1980.

BACKGROUND OF THE INVENTION

(1) Field of Invention

Circulation-enhancing drugs, substituted piperazine compounds useful forsaid purpose, preparation thereof, compositions containing the same, andmethod of using the same for the said purpose.

(2) Prior Art

Upon comparison with the known and accepted Cinnarizine (Arch. Int.Pharmacodyn. Ther. 204, 37, 1973), a known circulation stimulant, thepiperazines according to the invention show a superiorcirculation-enhancing action, especially in the brain. When contrastedwith the disubstituted benzyl piperazines reported to have adrenolyticor antihistaminic action in J. Med. Chem. 6 (5), 1963, pages 541-544,the compounds according to the invention have been found to becharacterized by a strong circulation-enhancing action, especially onthe cerebrovascular system. Although the N-substituted trialkylbenzylpiperazines known from DE-OS No. 27 14 996 are reported to havecardiovascular properties, they cannot be compared with the compoundsaccording to the invention, either with regard to chemical constitutionor with regard to action. The same statement is true with respect to themore complex substituted piperazines of DE-OS No. 25 11 022. See alsoChemical Abstracts 59 (1963), items 12804b and 12825e, for abstracts ofthe J. Med. Chem. article and the corresponding French Pat. No.1,318,449.

OBJECTS OF THE INVENTION

It is an object of the present invention to provide novelcirculation-enhancing compounds. It is a further object of the presentinvention to provide certain novel N-(trimethoxybenzyl)-piperazineswhich are useful as circulation-enhancing agents. It is a further objectof the invention to provide a method for the preparation of suchcompounds, pharmaceutical compositions of such compounds, and a methodof using the said novel compounds for the said circulation-enhancingpurpose. Additional objects will become apparent hereinafter, and stillother objects will be apparent to one skilled in the art to which thisinvention appertains.

SUMMARY OF THE INVENTION

Novel N-(trimethoxybenzyl)-piperazines of the formula: ##STR3## whereinA= ##STR4## wherein R is trifluoromethyl, hydroxy, nitro, halogen,lower-alkyl, or lower-alkoxy;

R' is hydrogen, trifluoromethyl, halogen, lower-alkyl, or lower-alkoxy;

R" is hydrogen or lower-alkoxy,

or wherein R and either R' or R" together stand for lower-alkylenedioxy, and acid addition salts thereof, a method of preparing same,pharmaceutical compositions thereof, and a method of enhancingcirculation, especially cerebrovascular circulation, therewith, are thesubject of the present invention.

These N-(trimethoxybenzyl)-piperazines of the foregoing general formula,including their inorganic and organic acid addition salts, have beenprepared and found to possess a marked stimulating action on mamalliancirculation, especially cerebrovascular blood supply, do not showuntoward side-effects, and may therefore be beneficially employed inhuman and veterinary medicine. They may be administered orally, e.g., astablets, capsules, syrups, or solutions, or by the parenteral route,preferably in the form of a water-soluble salt. They are also suitablefor combination with other drugs which act upon the vascular system,such as nicotinic acid and its esters, or with other activepharmaceutical principles.

IN GENERAL

Preferably, in the foregoing formula, lower-alkyl and lower-alkoxycomprise from one to four carbon atoms, inclusive, and preferablyhalogen comprises fluorine and chlorine, and lower-alkylene dioxycomprises one through four carbon atoms in the alkylene group. Otherlower-alkyl, lower-alkoxy, halogen, and lower-alkylene atoms or groupsmay be present in the compounds of the invention, but are not preferred.Lower-alkyl and lower-alkoxy may, as usual, have from one to eightcarbon atoms, inclusive; halogen may, as usual, include not onlychlorine and fluorine, but also bromine and iodine; and lower-alkylenemay, as usual, include methylene through octylene groups. However, aspreviously stated, fluorine and chlorine are preferred, lower-alkyl suchas methyl, ethyl, propyl, isopropyl, butyl, isobutyl, and so on, arepreferred, methoxy, ethoxy, propoxy, isopropoxy, butoxy, and the likeare preferred, and methylene, ethylene, propylene, and butylene aresimilarly preferred in the alkylene substituent. Still moreparticularly, among the groups preferred for R are the following:fluorine, methyl, methoxy, ethyl, ethoxy, hydroxy, chloro, nitro, andtrifluoromethyl. Preferred groups within the scope of R' are:trifluoromethyl, chloro, methyl, methoxy, and hydrogen. Preferred groupswithin the scope of R" are: methoxy and hydrogen. As already indicated,when the substituent R and either R' or R" are located on adjacentcarbon atoms of the phenyl ring, another preferred substituent may bemethylenedioxy. Further, of the compounds of the present invention,those having at least two substituents in the phenyl group constitutingthe radical "A", as well as those compounds wherein the said phenylradical is monosubstituted with a substituent other than lower-alkyl,are preferred, in which case the trifluoromethyl, fluoro, chloro,methoxy, ethoxy, and hydroxy substituents are especially preferred.

MANUFACTURING PROCESS

The new N-(trimethoxybenzyl)-piperazines according to the invention canbe manufactured according to either of two procedures, as outlinedgenerally hereinafter and employed specifically in the Examples whichfollow.

Method A ##STR5## Equimolar volumes of 3,4,5-trimethoxybenzyl halide,e.g., bromide or chloride, the selected substituted N-phenylpiperazine,an acid-binding agent such as sodium carbonate, sodium bicarbonate,triethylamine, or an excess of the basic component, are dissolved orsuspended in a solvent such as dimethyl formamide. The reaction takesplace upon heating at elevated temperature, preferably under reflux,within a few hours. Insoluble matter is removed by filtration,centrifugation, or decantation, and the solvent is evaporated. Theresidue is recrystallized from a suitable solvent or, if an acidaddition salt is desired to be produced, the crude reaction product ismixed with the respective acid, the resulting salt being recrystallizedfrom a suitable solvent. The yields by this method range between 40 and90% of the theoretical value. Method B ##STR6## One mol of the selectedsubstituted N,N-bis(2-halo, e.g., bromo or chloroethyl)aniline isheated, preferably with an excess, e.g., 1.5 to 2.5 mol, of3,4,5-trimethoxybenzylamine at an elevated temperature, e.g., to about50°-180° C. With preparations which can be stirred only with difficultyand/or which tend to darkening, an inert diluent, e.g., diphenyl, may beused, or a high-boiling hydrocarbon mixture and/or an inert protectivegas such as nitrogen may be employed.

After a reaction time of 2-24 hours, the reaction mixture is allowed tocool and, after addition of base, e.g., NaOH, the unreacted3,4,5-trimethoxybenzylamine and, if necessary, the diluent is distilledover.

After appropriate purification, the amine may be used again. Furtherprocessing of the starting material may be carried out according toMethod A. The yields are 40-95% of the theoretical value, based upon theN,N-bis(2-haloethyl)aniline employed.

The exact solvent, reaction temperature, and the exact reaction time isnot critical according to either procedure except for attainment ofmaximum yields and conversions.

DETAILED DESCRIPTION OF THE INVENTION

The following Examples are given by way of illustration only, but arenot to be construed as limiting.

EXAMPLE 1

3.53 g of N-(4-fluorophenyl)-N,N-bis-(2-chloroethyl)-amine and 7 g of3,4,5-trimethoxybenzyl amine is heated to 120° C. for 8 hours under N₂atmosphere. After cooling of the reaction mixture 50 ml of 1 N NaOH isadded, and the excess 3,4,5-trimethoxybenzyl amine removed bydistillation with steam.

After drying of the residue by steam, it is mixed with methanol andhydrochloric acid gas introduced in the solution. After sucking off anddrying of the resulting precipitate, 3.6 g ofN-(3,4,5-trimethoxy-benzyl)-N'-(4-fluorophenyl)-piperazine hydrochlorideis obtained. Mp: 270° C.

Elementary analysis: C--calculated: 60.52%, found: 60.42%.H--calculated: 6.60%, found: 6.48%. N--calculated: 7.06%, found: 6.96%.Cl--calculated: 8.93%, found: 8.88%.

EXAMPLE 2

8.66 g of 3,4,5-trimethoxybenzyl chloride, 7.05 g ofN-(2-methylphenyl)-piperazine and 7.00 g of finely-powdered KOH isboiled for 8 hours in 50 ml of dimethyl formamide under reflux.

After sucking off insoluble matter the filtrate is evaporated todryness, the residue is dissolved in methanol, hydrochloric acid gas isintroduced into the solution and the precipitate sucked off. 8.00 g ofN-(3,4,5-trimethoxybenzyl)-N'-(2-methylphenyl)-piperazine is obtained.Mp.: 89° C.

Elementary analysis: C--calculated: 70.76%, found: 70.96%.H--calculated: 7.92%, found: 7.88%. N--calculated: 7.86%, found: 7.87%.

The hydrochloride is obtained by redissolving the free base and furthertreatment with hydrogen chloride.

EXAMPLE 3

8.66 g of 3,4,5-trimethoxybenzyl chloride and 7.73 g ofN-(3-methoxyphenyl)-piperazine and 7.00 g of K₂ CO₃ is reacted andprocessed according to example 2.

8.00 g of N-(3,4,5-trimethoxy-benzyl)-N'-(3-methoxyphenyl)-piperazinehydrochloride is obtained. Mp.: 242° C.

Elementary analysis: C--calculated: 61.68%, found: 61.30%.H--calculated: 7.15%, found: 7.01%. N--calculated: 6.85%, found: 6.73%.Cl--calculated: 8.67%, found: 8.63%.

EXAMPLE 4

8.3 g of 3,4,5-trimethoxybenzyl chloride and 3.8 g ofN-(2-ethylphenyl)-piperazine and 3.5 g of K₂ CO₃ are reacted andprocessed according to example 2. 6.5 g ofN-(3,4,5-trimethoxy-benzyl)-N'-(2-ethylphenyl)-piperazinedihydrochloride is obtained. Mp.: 179° C.

Elementary analysis: C--calculated: 59.65%, found: 59.45%.H--calculated: 7.28%, found: 7.26%. N--calculated: 6.32%, found: 6.24%.Cl--calculated: 16.00%, found: 15.90%.

EXAMPLE 5

8.3 g of 3,4,5-trimethoxybenzyl chloride and 4.1 g ofN-(2-ethoxyphenyl)-piperazine and 3.5 g of K₂ CO₃ are reacted andprocessed according to example 2. 7.2 g ofN-(3,4,5-trimethoxy-benzyl)-N'-(2-ethoxyphenyl)-piperazinedihydrochloride is obtained. Mp.: 212° C.

Elementary analysis: C--calculated: 57.52%, found: 57.34%.H--calculated: 7.02%, found: 6.82%. N--calculated: 6.10%, found 6.01%.Cl--calculated: 15.43%, found: 15.63%.

EXAMPLE 6

8.3 g of 3,4,5-trimethoxybenzyl chloride and 4.15 g ofN-(2-nitrophenyl)-piperazine and 3.5 g of K₂ CO₃ are reacted andprocessed according to example 2. 5.5 g ofN-(3,4,5-trimethoxy-benzyl)-N'-(2-nitrophenyl)-piperazine hydrochlorideis obtained. Mp.: 248° C.

Elementary analysis: C--calculated: 56.67%, found: 56.68%.H--calculated: 6.18%, found: 6.20%. N--calculated: 9.91%, found: 9.92%.Cl--calculated: 8.36%, found: 8.53%.

EXAMPLE 7

8.3 g of 3,4,5-trimethoxybenzyl chloride and 3.5 g ofN-(4-hydroxyphenyl)-piperazine and 3.5 g of K₂ CO₃ are reacted andprocessed according to example 2. 4.2 g ofN-(3,4,5-trimethoxy-benzyl)-N'-(4-hydroxyphenyl)-piperazinehydrochloride is obtained. Mp.: 268° C. (decomposition).

Elementary analysis: C--calculated: 60.83%, found: 61.02%.H--calculated: 6.88%, found: 6.75%. N--calculated: 7.09%, found: 7.16%.Cl--calculated: 8.98%, found: 9.14%.

EXAMPLE 8

4.33 g of 3,4,5-trimethoxybenzyl chloride and 3.93 g ofN-(2-chlorophenyl)-piperazine and 3.5 g of K₂ CO₃ are reacted andprocessed according to example 2. 5.0 g ofN-(3,4,5-trimethoxy-benzyl)-N'-(2-chlorophenyl)-piperazinedihydrochloride is obtained. Mp.: 225° C.

Elementary analysis: C--calculated: 58.12%, found: 57.99%.H--calculated: 6.34%, found: 6.25%. N--calculated: 6.78%, found: 6.69%.Cl--calculated: 17.15%, found: 17.02%.

EXAMPLE 9

3.85 g of N-(2-methoxyphenyl)-piperazine, 4.33 g of3,4,5-trimethoxybenzyl chloride and 3.5 g of K₂ CO₃ are reacted andprocessed according to example 2. 5.0 g ofN-(3,4,5-trimethoxy-benzyl)-N'-(2-methoxyphenyl)-piperazinedihydrochloride is obtained. Mp.: 219° C.

Elementary analysis: C--calculated: 56.63%, found: 56.72%.H--calculated: 6.79%, found: 6.76%. N--calculated: 6.29%, found: 6.28%.Cl--calculated: 15.92%, found: 15.91%.

EXAMPLE 10

3.85 g of N-(4-methoxyphenyl)-piperazine, 4.33 g of3,4,5-trimethoxybenzyl chloride and 3.5 g of K₂ CO₃ are reacted andprocessed according to example 2. 4.5 g ofN-(3,4,5-trimethoxy-benzyl)-N'-(4-methoxyphenyl)-piperazinedihydrochloride is obtained. Mp.: 242° C.

Elementary analysis: C--calculated: 56.63%, found: 55.60%.H--calculated: 6.79%, found: 6.57%. N--calculated: 6.29%, found: 6.94%.Cl--calculated: 15.92%, found: 15.42%.

EXAMPLE 11

3.53 g of N-(2-fluorophenyl)-N,N-bis-(2-chloroethyl)-amine and 7 g of3,4,5-trimethoxybenzyl amine are reacted and processed according toexample 1.

3.5 g of N-(3,4,5-trimethoxy-benzyl)-N'-(2-fluorophenyl)-piperazinehydrochloride is obtained. Mp.: 240° C.

Elementary analysis: C--calculated: 60.54%, found: 60.42%.H--calculated: 6.60%, found: 6.48%. N--calculated: 7.06%, found: 6.96%.Cl--calculated: 8.93%, found: 8.88%.

EXAMPLE 12

8.66 g of 3,4,5-trimethoxybenzyl chloride, 7.05 g ofN-(3-methylphenyl)-piperazine and 7.00 g of finely powdered KOH arereacted and processed according to example 2.

8.00 g of N-(3,4,5-trimethoxy-benzyl)-N'-(3-methylphenyl)-piperazinehydrochloride is obtained. Mp.: 251° C.

Elementary analysis: C--calculated: 64.19%, found: 64.30%.H--calculated: 7.44%, found: 7.46%. N--calculated: 7.13%, found: 7.09%.Cl--calculated: 9.02%, found: 8.86%.

EXAMPLE 13

8.66 g of 3,4,5-trimethoxybenzyl chloride, 7.05 g ofN-(4-methylphenyl)-piperazine and 7.00 g of finely powdered KOH arereacted and processed according to example 2.

8.00 g of N-(3,4,5-trimethoxy-benzoyl)-N'-(4-methylphenyl)-piperazinehydrochloride is obtained. Mp: 255° C.

Elementary analysis: C--calculated: 64.19%, found: 64.44%.H--calculated: 7.44%, found: 7.41%. N--calculated: 7.13%, found: 7.14%.Cl--calculated: 9.02%, found: 8.88%.

EXAMPLE 14

50 ml of dimethyl formamide, 8.64 g of 3,4,5-trimethoxybenzyl chloride,7.60 g of N-(3,4-dimethylphenyl)-piperazine and 7.00 g of K₂ CO₃ areboiled for 8 hours under reflux. After sucking off insoluble matter thefiltrate is evaporated to dryness and the residue is dissolved inmethanol. Subsequently hydrochloric acid gas is introduced in thesolution and the precipitate sucked off. After drying 10.4 g ofN-(3,4,5-trimethoxybenzyl)-N'-(3,4-dimethylphenyl)-piperazinehydrochloride. Mp: 242° C.

Elementary analysis: C--calculated: 64.92%, found: 64.61%.H--calculated: 7.68%, found: 7.94%. N--calculated: 6.88%, found: 6.70%.Cl--calculated: 8.71%, found: 8.86%.

EXAMPLE 15

3.23 g ofN-(3-trifluoromethyl-4-chlorophenyl)-N,N-bis-(2-chloroethyl)-amine and 7g of 3,4,5-trimethoxybenzyl amine are heated to 120° C. under N₂atmosphere for 8 hours. After cooling of the reaction mixture 50 ml of 1N NaOH is added, excess 3,4,5-trimethoxybenzyl amine being removed bydistillation by steam.

After evaporation of the residue to dryness it is mixed with methanol,and hydrochloric acid gas is introduced in the solution.

After sucking off and drying the resulting precipitate, 3.6 g ofN-(3,4,5-trimethoxy-benzyl)-N'-(3-trifluoromethyl-4-chlorophenyl)-piperazinehydrochloride is obtained. Mp. 228° C.

Elementary analysis: C--calculated: 52.39%, found: 52.22%.H--calculated: 5.23%, found: 5.20%. N--calculated: 5.82%, found: 5.70%.F--calculated: 11.84%, found: 11.84%. Cl--calculated: 7.36%, found:7.41%. Cl⁻ --calculated: 7.36%, found: 7.26%.

EXAMPLE 16

9.00 g of 3,4,5-trimethoxybenzyl chloride and 8.20 g ofN-(3,4-methylenedioxyphenyl)-piperazine and 10.00 g of K₂ CO₃ arereacted and processed according to example 14.

13.00 g of N-(3,4,5-trimethoxy-benzyl)-N'-(3,4-methylenedioxyphenyl)-piperazine dihydrochloride is obtained. Mp.: 235° C.

Elementary analysis: C--calculated: 54.90%, found: 52.86%.H--calculated: 6.14%, found: 6.22%. N--calculated: 6.09%, found: 5.87%.Cl--calculated: 15.43%, found: 14.70%.

EXAMPLE 17

13.50 g of 3,4,5-trimethoxybenzyl chloride, 17.31 g ofN-(3,4,5-trimethoxyphenyl)-piperazine and 15.00 g of K₂ CO₃ are reactedand processed according to example 14.

10.00 g ofN-(3,4,5-trimethoxy-benzyl)-N'-(3,4,5-trimethoxyphenyl)-piperazinehydrochloride is obtained. Mp.: 216° C.

Elementary analysis: C--calculated: 58.90%, found: 58.73%.H--calculated: 7.09%, found: 7.09%. N--calculated: 5.97%, found: 5.95%.Cl--calculated: 7.56%, found: 7.46%.

EXAMPLE 18

9.00 g of 3,4,5-trimethoxybenzyl chloride, 11.92 g ofN-(3,4-di-trifluoromethylphenyl)-piperazine and 10.00 g of K₂ CO₃ arereacted and processed according to example 14.

14.2 g ofN-(3,4,5-trimethoxybenzyl)-N'-(3,5-di-trifluoromethylphenyl)piperazinehydrochloride is obtained. Mp.: 247° C.

Elementary analysis: C--calculated: 51.31%, found: 51.15%.H--calculated: 4.89%, found: 4.78%. N--calculated: 5.44%, found: 5.36%.F--calculated: 22.14%, found: 22.31%. Cl⁻ --calculated: 6.89%, found:6.88%.

EXAMPLE 19

11.0 g of 3,4,5-trimethoxybenzyl chloride, 9.51 g ofN-(2,6-dimethylphenyl)-piperazine and 7.00 g of K₂ CO₃ are reacted andprocessed according to example 14.

8.6 g of N-(3,4,5-trimethoxy-benzyl)-N'-(2,6-dimethylphenyl)-piperazinehydrochloride is obtained. Mp.: 218° C.

Elementary analysis: C--calculated: 64.93%, found: 65.24%.H--calculated: 7.68%, found: 7.84%. N--calculated: 6.88%, found 6.77%.Cl--calculated: 8.73%, found: 8.12%.

EXAMPLE 20 Additional Variations

In the same manner as given in the preceding examples, additionalcompounds according to the invention, having further variations in the"A" moiety thereof, in particular with respect to the substituents andnumber of substituents in the phenyl radical comprising the Group "A",are produced from the appropriate starting materials as set forth under"Manufacturing Process", further variations being infinitely possiblebetween the substituents designated R, R', and R", with respect to theexact radical signified thereby, the exact position in the ring, therelative positions of the substituents in the benzene ring, and withrespect to the ultimate product, whether it be the free base or aselected acid addition salt thereof. Obviously, the substituents may bepresent in different and varying ring positions, both individually andwith respect to each other when more than one substituent is present,and different substituents, such as propyl or butyl, propoxy or butoxy,and so on, may be present in one or more positions of the benzene ring,in accord with the definitions of the substituents R, R' and R" givenpreviously, depending only upon the judicious selection of the ringpositions and the substituents present in the starting reactantcontaining the variable moiety "A", as set forth previously under"Manufacturing Process" herein, as well as the selection of the finalform of the product, that is, whether it will be in the form of a freebase or in the form of a selected acid addition salt thereof and, if tobe in the form of an acid addition salt thereof, which particular salt,and whether of an organic or of an inorganic nature, all of which willimmediately be apparent and within the ability of one skilled in theart.

When isolating these and other compounds of Formula I in the form of anacid addition salt, the acid is preferably selected so as to contain ananion which is non-toxic and pharmacologically acceptable, at least inusual therapeutic doses. Representative salts which are included in thispreferred group are the hydrochlorides, hydrobromides, sulphates,acetates, phosphates, nitrates, methanesulphonates, ethanesulphonates,lactates, citrates, tartrates or bitartrates, and maleates of the aminesof Formula I. Other acids are likewise suitable and may be employed ifdesired. For example, fumaric, benzoic, ascorbic, succinic, salicylic,bismethylenesalicylic, propionic, gluconic, malic, malonic, mandelic,cinnamic, citraconic, stearic, palmitic, itaconic, glycolic,benzenesulphonic, and sulphamic acids may also be employed as acidaddition salt-forming acids.

In the foregoing Formula I and elsewhere herein, the term "lower-alkyl",and the lower-alkyl radical present in the term "lower-alkoxy", refersto alkyl radicals containing up to and including eight (8) carbon atoms,and preferably no more than four (4) carbon atoms. The radicals may haveeither straight or branched chain structure. Typical examples aremethyl, ethyl, propyl, isopropyl, butyl, isobutyl, amyl, hexyl, heptyl,octyl, or the like.

PHARMACOLOGY

The compounds of the invention possess beneficial pharmacologicalproperties, and are effective pharmaceutical agents. The compoundsexhibit a circulation-stimulating effect.

The circulation-enhancing activity of the substances according to theinvention can be demonstrated by known methods. One of these methods isthe measurement of cerebrovascular resistance on the rabbit according toH. Hutten and P. Vaupel (cf. die Medizinische Welt 28, 1567, 1977). Thetherapeutic effect is expressed in terms of decrease in vascularresistance.

For this purpose 0.1 ml of a 1% solution of the test substance, i.e.,according to the invention, was administered to the rabbit by arterialapplication. The decrease in vascular resistance (R) and the relativedecrease in vascular resistance (ΔR%) were recorded and expressed in mmHg min/l or in the valid S.I. unit k Pa min/ml, i.e., absolute decreaseof resistance x time.

From Arch. Int. Pharmacodyn. Ther. 204, 37 (1973), the use ofCinnarizine as a circulation-stimulating agent is already known. Theactivity of this compound was tested by means of the aforementionedmethod. Comparative tests have however demonstrated that theN-(trimethoxybenzyl)-piperazines according to the invention show anincomparably higher decrease in vascular resistance (ΔR%), as can beobserved from the following Tables, wherein the test results incomparison with Cinnarizine are given.

                  TABLE 1                                                         ______________________________________                                        (Examples 1-13)                                                               Compound according                                                                              Absolute decrease of                                        to the invention  vascular resistance                                         R (R' and R" = H) R (mm Hg min/l)                                                                              ΔR %                                   ______________________________________                                        Compound of                                                                   comparison (Cinnarizine)                                                                        2,9            19,3                                         p. Fluoro-        4,6            26,4                                         m. Methoxy-       3,0            28,5                                         o. Fluoro-        3,0            23,0                                         o. Chloro-        3,0            27,9                                         o. Methyl-        3,3            24,5                                         m. Methyl-        3,2            22,0                                         p. Methyl-        3,3            23,0                                         o. Ethyl-         3,0            21,7                                         o. Ethoxy-         2,85          20,4                                         p. Hydroxy-       2,8            19,5                                         o. Nitro-         3,1            20,6                                         o. Methoxy-        2,94          22,2                                         p. Methoxy-        3,90          27,8                                         ______________________________________                                    

The Table shows that the N-(trimethoxybenzyl)-N'-(monosubstitutedphenyl)-piperazines according to the invention effect an incomparablyhigher decrease of vascular resistance than the substance of comparison.

The following Table 2 shows the mean effective ED₅₀ and LD₅₀ values aswell as the therapeutic indices of the piperazines according to theinvention in comparison with the Cinnarizine values:

                  TABLE 2                                                         ______________________________________                                         (Examples 1-13)                                                              The calculation of the therapeutic indices was based on the                   respective i.v. toxicities:                                                    Substance R (R' and R" = H)                                                                  ED.sub.50 mg/kg                                                                          LD.sub.50 mg/kg                                                                          ##STR7##                                ______________________________________                                        Cinnarizine    0,6        670        1110                                     as comparison                                                                 p. Fluoro-     0,37       580        1570                                     m. Methoxy-    0,42       850        2010                                     o. Fluoro-     0,40       920        2280                                     o. Chloro-     0,38       810        2130                                     o. Methyl-     0,48       700        1450                                     m. Methyl-     0,46       700        1520                                     p. Methyl-     0,44       720        1630                                     o. Ethyl-      0,40       900        2240                                     o. Ethoxy-     0,45       900        1990                                     p. Hydroxy-    0,45       1260       2800                                     o. Nitro-      0,50       650        1300                                     o. Methoxy-    0,42       1150       2750                                     p. Methoxy-    0,30       910        3050                                     ______________________________________                                    

                  TABLE 3                                                         ______________________________________                                         (Examples 1-13)                                                              Acute toxicities LD.sub.50 (mouse oral) mg/kg                                 Substance R   24 h mg/kg                                                                              14 days mg/kg                                         ______________________________________                                        p. Fluoro-    349,6     274,9                                                 m. Methoxy-   410,7     285,2                                                 o. Chloro-    294,8     255,2                                                 m. Methyl-    452,5     310,3                                                 p. Methyl-    458,6     312,1                                                 o. Methyl-    456,7     310,8                                                 o. Ethyl-     456,2     311,0                                                 o. Ethoxy-    410,7     266,2                                                 p. Hydroxy-   306,2     244,8                                                 o. Nitro-     273,7     200,8                                                 ______________________________________                                    

                  TABLE 4                                                         ______________________________________                                        (Examples 14-19)                                                                                  Absolute decrease                                                             in vascular                                               Compound according to                                                                             resistance R                                              the invention       (mm Hg min/l)                                                                              ΔR %                                   ______________________________________                                             Compound of                                                                  comparison (Cinnarizine)                                                                          2.9          19.3                                     (1) N--(3,4,5-trimethoxy-benyzyl)-                                                                    3.0          24.3                                         N'--(3,4-dimethylphenyl)-                                                     piperazine                                                                (2) N--(3,4,5-trimethoxy-benzyl)-                                                                     3.5          26.3                                         N'--(3-trifluoromethyl-4-                                                     chlorophenyl)-piperazine                                                  (3) N--(3,4,5-trimethoxy-benzyl)-                                                                     3.1          22.0                                         N'--(3,4-methylenedioxy-                                                      phenyl)-piperazine                                                        (4) N--(3,4,5-trimethoxy-benzyl)-                                                                     3.0          21.5                                         N'--(3,4,5-trimethoxy-phenyl)-                                                piperazine                                                                (5) N--(3,4,5-trimethoxy-benzyl)-                                                                     3.3          20.6                                         N'--(3,5-di-trifluoromethyl-                                                  phenyl)-piperazine                                                        (6) N--(3,4,5-trimethoxy-benzyl)-                                                                     3.2          23.0                                         N'--(2,6-dimethyl-phenyl)-                                                    piperazine                                                                ______________________________________                                    

The therapeutic range of the substances according to the invention canagain be described as excellent, since the LD₅₀ values lie in afavorable range, as is shown by the results of acute toxicity tests onthe mouse after oral application.

                  TABLE 5                                                         ______________________________________                                         (Examples 14-19)                                                             Acute toxicity oral (mouse) LD.sub.50                                         No. of substance                                                                             24 h mg/kg                                                                              14 days mg/kg                                        ______________________________________                                        1              347.9     263.3                                                2              328.3     283.2                                                3              312.1     296.0                                                4              347.7     347.7                                                5              300.1     280.2                                                6              347.7     264.7                                                ______________________________________                                    

                  TABLE 6                                                         ______________________________________                                        (Examples 14-19)                                                              No. of substance                                                                         ED.sub.50 mg/kg                                                                           LD.sub.50 mg/kg                                                                          Ther. Index                                 ______________________________________                                        Cinnarizine as                                                                           0.6         670        1110                                        comparison                                                                    1          0.02        260        13000                                       2          0.09        283        3150                                        3          0.11        297        2700                                        4          0.05        350        7000                                        5          0.05        280        5600                                        6          0.07        265        3800                                        ______________________________________                                    

COMPOSITIONS AND METHOD OF TREATING

The novel compounds of the present invention are usually preferablyemployed in the form of their pharmaceutically-acceptable acid additionsalts, e.g., their hydrochlorides, hydrobromides, or the like. The saltform is generally the best form for pharmaceutical formulations.Innumerable other pharmaceutically-acceptable acid addition salts can beprepared from the free base or from another acid addition salt, e.g.,the hydrochloride, in a conventional manner. One acid addition salt,even if not pharmaceutically-acceptable, can readily be converted toanother salt which is pharmaceutically-acceptable in known manner, ifdesired. The solution of any salt, after alkalization, can be extractedwith a suitable solvent, e.g., ether, and dried, as with sodiumsulphate, to give a solution of the selected free base, whereafter thenovel piperazine compound according to the present invention can beprecipitated as a salt, preferably with a pharmaceutically-acceptableacid, for example, hydrochloric or hydrobromic acid, oxalic acid, maleicacid, citric acid, tartaric acid, sulphuric acid, methanesulphonic acid,or the like. Some forms of compositions according to the presentinvention, comprising a compound of the present invention together witha non-toxic pharmaceutically-acceptable carrier, in addition to theactive ingredient, follow. A wide variety of pharmaceutical formssuitable for many modes of administration and dosages may be employedaccording to the skill of the art.

The method of the present invention comprises the administration,preferably by the oral or parenteral route, of an activecirculation-enhancing compound according to the present invention,preferably in the form of a composition and including apharmaceutically-acceptable carrier, but possibly alone, as in the caseof administering the active ingredient in capsulated form, in acirculation-enhancing amount, to a mammalian subject, including a humanbeing, in need of such circulation enhancement or stimulation. In thecase of compositions, the active agents of the invention are mostconveniently administered in the form of such compositions containingabout 0.01 to 67%, preferably 0.04 to 12.15%, by weight of activeingredient. Numerous such formulations are representatively illustratedin U.S. Pat. No. 3,402,244. The compounds and their non-toxic salts,especially the hydrochlorides, may be advantageously employed forcirculation stimulation in amounts approximating those employed for theknown product Cinnarizine, a clinically-useful compound used forcomparative testing as reported herein, but dosages will generally besomewhat reduced in view of the superiority of the compounds of theinvention with respect to Cinnarizine. Parenteral dosages are usuallyless than oral dosages, but the compounds and their administration aresubject to wide variations in optimum daily and unit dosages, due tovariations in patient body weight, condition, and ancillary factors, sothat the exact dosage, both unit and daily, will of course have to bedetermined according to established medical principles by the physicianor veterinarian in charge. In addition, the active ingredients of thepresent invention or compositions containing the same may either beadministered together with or include other physiologically activematerials and/or medicaments, such as buffering agents, antacids,sedatives, stimulants, anticholinergics, analgesics, or the like.

The following formulations are representative for all of thepharmacologically-active compounds of the invention, and are not to beconstrued as limiting:

FORMULATION AND ADMINISTRATION

The present invention also relates to new preparations containing thecompounds according to the invention as active components. Whenmanufacturing the preparations according to the invention the activeingredient is incorporated in a suitable carrier, e.g., a pharmaceuticalcarrier. Examples for suitable pharmaceutical carriers which may be usedin the formulation of the preparations according to the invention arestarch, gelatin, magnesium carbonate, lactose, and malt.

The present invention also relates to liquid preparations, and examplesof suitable liquid carriers are ethyl alcohol, propylene glycol,glycerin, and glucose sirup.

The preparations according to the invention will be further illustratedby the following examples:

1. Drug capsules:

Capsules containing 25 mg, 50 mg and 100 mg of the active ingredientwere produced.

Typical mixtures for encapsulation:

    ______________________________________                                                           25 mg per capsule                                          ______________________________________                                        Active ingredient (from Examples)                                                                  25.0                                                     Lactose              251.7                                                    Starch               129.0                                                    Magnesium stearate   4.3                                                      total                410.0 mg                                                 ______________________________________                                    

Additional capsule formulations have preferably a higher active contentand are given in the following:

    ______________________________________                                                           100 mg per capsule                                         ______________________________________                                        Active ingredient (from Examples)                                                                  100.0                                                    Lactose              306.5                                                    Starch               99.2                                                     Magnesium stearate   4.3                                                      total                510.0 mg                                                 ______________________________________                                    

The active ingredient chosen is preferably mixed with lactose, starchand magnesium stearate, the mixture being encapsulated.

2. Tablets:

A typical formulation for a tablet containing 50 mg of the activeingredient per tablet is the following.

This formulation may also be used for other active contents by adjustingthe weight of dicalcium phosphate:

    ______________________________________                                                           50 mg per tablet                                           ______________________________________                                        Active ingredient (from Examples)                                                                  50.0                                                     Cornstarch           13.6                                                     Cornstarch (Paste)   3.4                                                      Lactose              79.2                                                     Dicalcium phosphate  68.0                                                     Calcium stearate     0.8                                                      total                215.0 mg                                                 ______________________________________                                    

The adjuvants are intimately mixed with the active ingredient, theresulting mixture being subsequently granulated by using water asgranulating agent. The still moist granules are passed through a sieve(inside width of mesh 2.36 cm) and dried. The dried granules are mixedwith calcium stearate and pressed.

3. Injectable 2% sterile solutions:

    ______________________________________                                                            per cm.sup.3                                              ______________________________________                                        Active ingredient (from Examples)                                                                   20 mg                                                   Preservative, e.g., chlorobutanol                                                                   0.5% weight/vol.                                        Water                 if necessary                                            ______________________________________                                    

The solution is prepared, cleared by filtration, filled into tubes orampoules, closed and heated in an autoclave.

EXAMPLE 21

4.32 g of 3,4,5-trimethoxybenzyl chloride and 3.24 g of N-phenylpiperazine is dissolved in 50 ml of dimethyl formamide in the presenceof 3.0 g of water-free soda and is boiled for 8 hours under reflux.After sucking off insoluble matter the filtrate is evaporated todryness, the residue is dissolved in methanol. Subsequently hydrochloricacid gas is introduced in the solution and the precipitate sucked off.After drying 3.4 g of N-(3,4,5-trimethoxy-benzyl)-N'-phenyl-piperazinehydrochloride is obtained.

Anal. Calcd. %: C,69.39; H,7.18; N,7.39; Cl,9.36. Found %: C,63.44;H,7.18; N,7.35; Cl,9.27. Mp.: 260° C.

This compound is a circulation stimulant according to the Hutten andVaupel rabbit test procedure previously discussed herein. The absolutedecrease of vascular resistance R in mm. Hg. min/l which it effected was3.0 with a decrease of vascular resistance (ΔR %) of 23.2. Its oralacute toxicity in the mouse (LD₅₀) after 24 hours in 319.7 mg/kg andafter fourteen days is 265.2 mg/kg. This compound is accordingly usefulas the active ingredient in pharmaceutical compositions together with acarrier or diluent, and in the method of effecting enhancement orstimulation of circulation, both in accord with the foregoingdisclosure.

It is to be understood that the invention is not to be limited to theexact details of operation or exact compounds, compositions, methods, orprocedures shown and described, as obvious modifications and equivalentswill be apparent to one skilled in the art.

We claim:
 1. Method for the treatment of a subject in need ofenhancement or stimulation of circulation, comprising the step ofadministering to the subject a circulation-enhancing amount of acompound selected from the group consisting of(a)N-(trimethoxybenzyl)-N'-phenylpiperazines having the formula: ##STR8##wherein A= ##STR9## wherein R is trifluoromethyl, hydroxy, nitro,halogen, lower-alkyl, lower-alkoxy, or hydrogen;R' is hydrogen,trifluoromethyl, halogen, lower-alkyl, or lower-alkoxy; R" is hydrogenor lower-alkoxy, or wherein R and either R' or R" together stand forlower-alkylene dioxy, and (b) pharmaceutically-acceptable acid additionsalts thereof.
 2. The method of claim 1, wherein the compound isN-(3,4,5-trimethoxy-benzyl)-N'-phenylpiperazine or an acid addition saltthereof.
 3. Method for the treatment of a subject in need of enhancementor stimulation of circulation, comprising the step of administering tothe subject a circulation-enhancing amount of a compound selected fromthe group consisting of(a) N-(trimethoxybenzyl)-N'-phenylpiperazineshaving the formula: ##STR10## wherein A= ##STR11## wherein R istrifluoromethyl, hydroxy, nitro, halogen, lower-alkyl, orlower-alkoxy;R' is hydrogen, trifluoromethyl, halogen, lower-alkyl, orlower-alkoxy; R" is hydrogen or lower-alkoxy, or wherein R and either R'or R" together stand for lower-alkylene dioxy, and (b)pharmaceutically-acceptable acid addition salts thereof.
 4. Method ofclaim 3, wherein a pharmaceutically-acceptable acid addition salt of apiperazine compound is employed.
 5. The method of claim 3, wherein atleast one of R' and R" is other than hydrogen.
 6. The method of claim 3,wherein R is selected from the group consisting of trifluoromethyl,lower-alkoxy, halogen, hydroxy, and nitro.
 7. The method of claim 3,wherein R is fluoro or chloro.
 8. The method of claim 3, wherein R islower-alkoxy.
 9. The method of claim 3, wherein R is trifluoromethyl.10. A method of claim 3, wherein lower-alkyl and lower-alkoxy contain upto and including four (4) carbon atoms.
 11. A method of claim 4, whereinlower-alkyl and lower-alkoxy contain up to and including four (4) carbonatoms.
 12. A method of claim 5, wherein lower-alkyl and lower-alkoxycontain up to and including four (4) carbon atoms.
 13. A method of claim6, wherein lower-alkyl and lower-alkoxy contain up to and including four(4) carbon atoms.
 14. A method of claim 7, wherein lower-alkyl andlower-alkoxy contain up to and including four (4) carbon atoms.
 15. Amethod of claim 8, wherein lower-alkyl and lower-alkoxy contain up toand including four (4) carbon atoms.
 16. A method of claim 9, whereinlower-alkyl and lower-alkoxy contain up to and including four (4) carbonatoms.
 17. The method of claim 3 wherein the compound isN-(3,4,5-trimethoxybenzyl)-N'-(4-fluorophenyl)-piperazine or an acidaddition salt thereof.
 18. The method of claim 3 wherein the compound isN-(3,4,5-trimethoxybenzyl)-N'-(2-methylphenyl)-piperazine or an acidaddition salt thereof.
 19. The method of claim 3 wherein the compound isN-(3,4,5-trimethoxybenzyl)-N'-(3-methoxyphenyl)-piperazine or an acidsolution salt thereof.
 20. The method of claim 3 wherein the compound isN-(3,4,5-trimethoxybenzyl)-N'-(2-ethylphenyl)-piperazine or an acidaddition salt thereof.
 21. The method of claim 3 wherein the compound isN-(3,4,5-trimethoxybenzyl)-N'-(2-ethoxyphenyl)-piperazine or an acidaddition salt thereof.
 22. The method of claim 3 wherein the compound isN-(3,4,5-trimethoxybenzyl)-N'-(2-nitrophenyl)-piperazine or an acidaddition salt thereof.
 23. The method of claim 3 wherein the compound isN-(3,4,5-trimethoxybenzyl)-N'-(4-hydroxyphenyl)-piperazine or an acidaddition salt thereof.
 24. The method of claim 3 wherein the compound isN-(3,4,5-trimethoxybenzyl)-N'-(2-chlorophenyl)-piperazine or an acidaddition salt thereof.
 25. The method of claim 3 wherein the compound isN-(3,4,5-trimethoxybenzyl)-N'-(2-methoxyphenyl)piperazine or an acidaddition salt thereof.
 26. The method of claim 3 wherein the compound isN-(3,4,5-trimethoxybenzyl)-N'-(4-methoxyphenyl)-piperazine or an acidaddition salt thereof.
 27. The method of claim 3 wherein the compound isN-(3,4,5-trimethoxybenzyl)-N'-(2-fluorophenyl)-piperazine or an acidaddition salt thereof.
 28. The method of claim 3 wherein the compound isN-(3,4,5-trimethoxybenzyl)-N'-(3-methylphenyl)-piperazine or an acidaddition salt thereof.
 29. The method of claim 3 wherein the compound isN-(3,4,5-trimethoxybenzyl)-N'-(4-methylphenyl)-piperazine or an acidaddition salt thereof.
 30. The method of claim 3 wherein the compoundsis N-(3,4,5-trimethoxybenzyl)-N'-(3,4-dimethylphenyl)-piperazine or anacid addition salt thereof.
 31. The method of claim 3 wherein thecompound isN-(3,4,5-trimethoxybenzyl)-N'-(3-trifluoromethyl-4-chlorophenyl)-piperazineor an acid addition salt thereof.
 32. The method of claim 3 wherein thecompound isN-(3,4,5-trimethoxybenzyl)-N'-(3,4-methylenedioxyphenyl)-piperazine oran acid addition salt thereof.
 33. The method of claim 3 wherein thecompound isN-(3,4,5-trimethoxybenzyl)-N'-(3,4,5-trimethoxyphenyl)-piperazine or anacid addition salt thereof.
 34. The method of claim 3 wherein thecompound isN-(3,4,5-trimethoxybenzyl)-N'-(3,5-di-trifluoromethylphenyl)-piperazineor an acid addition salt thereof.
 35. The method of claim 3 wherein thecompound isN-(3,4,5-trimethoxybenzyl)-N'-(2,6-dimethylphenyl)-piperazine or an acidaddition salt thereof.
 36. The method of claim 4 wherein the compound isa hydrochloride acid addition salt.